Molecular Profiling of Syringocystadenocarcinoma Papilliferum Reveals RAS-Activating Mutations.

CONTEXT.­: Syringocystadenocarcinoma papilliferum (SCACP) is a rare adnexal carcinoma and the malignant counterpart of syringocystadenoma papilliferum (SCAP), which is commonly located on the head and neck and may arise in association with a nevus sebaceus. RAS mutations have been identified in both SCAP and nevus sebaceus. OBJECTIVE.­: To evaluate the clinicopathologic and molecular features of SCACPs, which have not been previously explored. DESIGN.­: We obtained 11 SCACPs from 6 institutions and reviewed the clinicopathologic features. We also performed molecular profiling using next-generation sequencing. RESULTS.­: The cohort comprised 6 women and 5 men with ages ranging from 29 to 96 years (mean, 73.6 years). The neoplasms occurred on the head and neck (n = 8; 73%) and extremities (n = 3; 27%). Three tumors possibly arose in a nevus sebaceus. A total of 4 cases showed at least carcinoma in situ (adenocarcinoma, n = 3; squamous cell carcinoma [SCC], n = 1), and 7 cases were invasive (SCC, n = 5; mixed adenocarcinoma + SCC, n = 2). A total of 8 of 11 cases (73%) had hot spot mutations consisting of HRAS (n = 4), KRAS (n = 1), BRAF (n = 1), TP53 (n = 4), ATM (n = 2), FLT3 (n = 1), CDKN2A (n = 1), and PTEN (n = 1). All 4 cases with HRAS mutations occurred on the head and neck, whereas the KRAS mutation occurred on the extremity. CONCLUSIONS.­: RAS-activating mutations were detected in 50% of the cases, of which most (80%) involved HRAS and occurred on the head and neck, which shows overlapping features with SCAP, supporting that a subset may arise as a result of malignant transformation and likely an early oncogenic event.

Pharmacokinetics, Efficacy, and Safety of a SARS-CoV-2 Antibody Treatment in Pediatric Participants: An Open-Label Addendum of a Placebo-Controlled, Randomized Phase 2/3 Trial.

INTRODUCTION: Bamlanivimab and etesevimab (BAM + ETE) are monoclonal antibodies (mAbs) effective in reducing COVID-19-related hospitalizations and all-cause mortality in adult participants at increased risk for severe disease. We present pharmacokinetic (PK), efficacy, and safety results from pediatric participants (< 18 years of age) with COVID-19 who were treated with BAM + ETE. METHODS: In an addendum to the phase 2/3 BLAZE-1 clinical trial (NCT04427501), pediatric participants received open-label weight-based dosing (WBD, n = 94) based on exposure-matching to the authorized dose of BAM + ETE in adult participants. For efficacy and safety assessments, placebo (n = 14) and BAM + ETE (n = 20)-treated adolescent participants (> 12 to < 18 years of age) from the BLAZE-1 trial were included in the overall pediatric population (N = 128). All participants had mild to moderate COVID-19 upon enrollment and ≥ 1 risk factor for severe COVID-19. The primary objective was to characterize the PK of BAM and ETE in the WBD population. RESULTS: The median age of the participants was 11.2 years, 46.1% were female, 57.9% were Black/African American, and 19.7% were Hispanic/Latino. The area under the curve for BAM and ETE in the WBD population was similar to that previously observed in adults. There were no COVID-19-related hospitalizations or deaths. All adverse events (AE) except one were mild or moderate, with one participant reporting a serious AE. CONCLUSION: WBD in pediatric participants achieved similar drug exposures compared to adult participants that received the authorized BAM + ETE dose. The pediatric efficacy and safety data were consistent with adults receiving mAbs for COVID-19. TRIAL REGISTRATION NUMBER: NCT04427501.

General Anesthetics in CAncer REsection Surgery (GA-CARES) randomized multicenter trial of propofol vs volatile inhalational anesthesia: protocol description.

BACKGROUND: Studies indicate that patients can be "seeded" with their own cancer cells during oncologic surgery and that the immune response to these circulating cancer cells might influence the risk of cancer recurrence. Preliminary data from animal studies and some retrospective analyses suggest that anesthetic technique might affect the immune response during surgery and hence the risk of cancer recurrence. In 2015, experts called for prospective scientific inquiry into whether anesthetic technique used in cancer resection surgeries affects cancer-related outcomes such as recurrence and mortality. Therefore, we designed a pragmatic phase 3 multicenter randomized controlled trial (RCT) called General Anesthetics in Cancer Resection (GA-CARES). METHODS: After clinical trial registration and institutional review board approval, patients providing written informed consent were enrolled at five sites in New York (NY) State. Eligible patients were adults with known or suspected cancer undergoing one of eight oncologic surgeries having a high risk of cancer recurrence. Exclusion criteria included known or suspected history of malignant hyperthermia or hypersensitivity to either propofol or volatile anesthetic agents. Patients were randomized (1:1) stratified by center and surgery type using REDCap to receive either propofol or volatile agent for maintenance of general anesthesia (GA). This pragmatic trial, which seeks to assess the potential impact of anesthetic type in "real world practice", did not standardize any aspect of patient care. However, potential confounders, e.g., use of neuroaxial anesthesia, were recorded to confirm the balance between study arms. Assuming a 5% absolute difference in 2-year overall survival rates (85% vs 90%) between study arms (primary endpoint, minimum 2-year follow-up), power using a two-sided log-rank test with type I error of 0.05 (no planned interim analyses) was calculated to be 97.4% based on a target enrollment of 1800 subjects. Data sources include the National Death Index (gold standard for vital status in the USA), NY Cancer Registry, and electronic harvesting of data from electronic medical records (EMR), with minimal manual data abstraction/data entry. DISCUSSION: Enrollment has been completed (n = 1804) and the study is in the follow-up phase. This unfunded, pragmatic trial, uses a novel approach for data collection focusing on electronic sources. TRIAL REGISTRATION: Registered (NCT03034096) on January 27, 2017, prior to consent of the first patient on January 31, 2017.

Localised chronic fibrosing vasculitis versus erythema elevatum diutinum.

A woman in her 70s was referred for a painless plaque on the shin, present for 2 years and progressing in thickness. Examination revealed a large erythematous to violaceous indurated plaque with cobblestone appearance. Biopsy revealed an inflammatory infiltrate of neutrophils with scattered histiocytes, lymphocytes, eosinophils and plasma cells interspersed with areas of lamellar fibrosis and focal areas of vascular damage, suggestive of a localised chronic fibrosing vasculitis of the skin. Localised chronic fibrosing vasculitis is a rare dermatosis, typically presenting as ulcerated violet-red nodules, which can appear histologically similar to erythema elevatum diutinum (EED), which typically presents as red-brown annular plaques. EED may have a predominance of neutrophils and granulomas, while chronic fibrosing vasculitis may have a sparse infiltrate of mixed inflammatory cells without granulomas. While dapsone is a first-line treatment for EED, there are no formal guidelines on the treatment of localised chronic fibrosing vasculitis. Given the neutrophils in this sample and similarities with EED, this patient was treated with oral dapsone, resulting in plaque improvement.

Cost of Intralesional Collagenase Clostridium Histiolyticum Therapy Versus Surgery for the Management of Peyronie's Disease: A Claims-Based Analysis (2009-2019).

BACKGROUND: Collagenase Clostridium histolyticum (CCH), which was approved by the FDA for the treatment of Peyronie's disease (PD) in 2013, may obviate the need for surgery but its historically high cost must be considered when offering CCH vs surgical intervention to affected patients. AIM: To compare trends of intralesional injections vs surgical treatment for PD and assess the contemporary cost of treatment with CCH vs surgical intervention. METHODS: We reviewed 2009-2019 MarketScan Commercial Claims data to identify all men 18 years and older with PD. CPT and HCPCS codes were used to identify PD treatments for each patient. Associated insurance claims in USD were summed for each treatment type. OUTCOMES: Total and out-of-pocket costs, as well as frequencies, for treatments were calculated on a yearly basis and the Cochran-Armitage test was used to compare frequencies before and after FDA approval of CCH. RESULTS: Of 89,205 men diagnosed with PD, 21,605 (24.2%) underwent treatment; most required only intralesional injections, however 1,519 (7.0%) received only surgical therapy and 1,951 (9.0%) required medical and surgical therapy. Intralesional CCH use sharply increased after its FDA-approval in 2013 with a concomitant fall of intralesional verapamil use. The use of both surgical plication and plaque grafting decreased steadily from 2009 to 2019. The median cost per patient for all 3 treatments increased over the study time-period: $1,856 to $3,196 for plication, $2,233 to $3,631 for plaque grafting, and $6,940 to $8,895 per cycle for CCH. Out-of-pocket median patient contribution for plication, plaque grafting, and per cycle intralesional CCH injection were similar over the study period and never exceeded $300. CLINICAL IMPLICATIONS: CCH is significantly more expensive than any surgical treatment option, however, the out-of-pocket patient contribution for surgery and CCH are similar. STRENGTHS & LIMITATIONS: This study incorporated all procedure costs and is the most contemporary, comprehensive, and accurate reflection of overall and out-of-pocket costs to patients for surgical and intralesional PD therapies. We anticipate these data to allow for a more complete discussion between patients and providers regarding their care. The use of a commercial claims database prohibited assessment of post-procedural costs and treatment outcomes. CONCLUSION: CCH use has increased significantly since its FDA approval in 2013 with out-of-pocket patient contribution comparable to surgical therapy despite significantly higher total treatment costs. Walton EL, Quinn TP, Mulloy E, et al. Cost of Intralesional Collagenase Clostridium Histiolyticum Therapy Versus Surgery for the Management of Peyronie's Disease: A Claims-Based Analysis (2009-2019). Sex Med 2022;10:100517.

Management of diffuse alveolar hemorrhage in the hematopoietic stem cell transplantation population: A systematic review.

Pulmonary complications post-hematopoietic stem cell transplantation (HSCT) such as diffuse alveolar hemorrhage (DAH) can occur in 2% to 14% of HSCT patients and have a mortality greater than 80%. Diffuse alveolar hemorrhage is considered to be an inflammatory response; therefore, HSCT patients are primarily treated with different types of systemic corticosteroids with varying dosages. Other treatments currently reported in the literature in conjunction with corticosteroids include aminocaproic acid, recombinant factor VIIa (rFVIIa), and etanercept. This review highlights appropriate frontline and adjunctive treatment options for HSCT patients with DAH and outcomes for each intervention. To perform the review, the PubMed database was searched from inception through March 19, 2021, to identify potential studies using the search terms DAH and HSCT, DAH and hematopoietic cell transplant (HCT), DAH and stem cell, lung injury and HSCT, and lung injury and HCT. When applicable, references from articles identified in the search were also reviewed for inclusion. Much of the data identified were limited to retrospective cohort studies and case series. Based on the data available, the treatment approach should consist of corticosteroid therapy with a suggested methylprednisolone dose of 250 mg daily followed by a 50% taper every 3 days. Intrapulmonary administration of rFVIIa and intravenous administration of aminocaproic acid could be considered as adjunctive agents in those patients who do not promptly respond to corticosteroid therapy. Due to a lack of data specific to HSCT patients who develop DAH and the risk of infectious complications, etanercept should be avoided. Future studies should be designed as randomized controlled trials and examine the use of adjunctive therapies in the upfront setting for HSCT patients with DAH.

Disparities in magnetic resonance imaging of the prostate for traditionally underserved patients with prostate cancer.

BACKGROUND: Prebiopsy magnetic resonance imaging (MRI) of the prostate improves detection of significant tumors, while decreasing detection of less-aggressive tumors. Therefore, its use has been increasing over time. In this study, the use of prebiopsy MRI among Medicare beneficiaries with prostate cancer was examined. It was hypothesized that patients of color and those in isolated areas would be less likely to undergo this approach for cancer detection. METHODS: Using cancer registry data from the Surveillance, Epidemiology, and End Results (SEER) program linked to billing claims for fee-for-service Medicare beneficiaries, men with nonmetastatic prostate cancer were identified from 2010 through 2015 with prostate-specific antigen (PSA) <30 ng/mL. Outcome was prebiopsy MRI of the prostate performed within 6 months before diagnosis (ie, Current Procedural Terminology 72197). Exposures were patient race/ethnicity and rural/urban status. Multivariable regression estimated the odds of prebiopsy prostate MRI. Post hoc analyses examined associations with the registry-level proportion of non-Hispanic Black patients and MRI use, as well as disparities in MRI use in registries with data on more frequent use of prostate MRI. RESULTS: There were 50,719 men identified with prostate cancer (mean age, 72.1 years). Overall, 964 men (1.9% of cohort) had a prebiopsy MRI. Eighty percent of patients with prebiopsy MRI lived in California, New Jersey, or Connecticut. Non-Hispanic Black men (0.6% vs 2.1% non-Hispanic White; odds ratio [OR], 0.28; 95% CI, 0.19-0.40) and men in less urban areas (1.1% vs 2.2% large metro; OR, 0.65; 95% CI, 0.44-0.97) were less likely to have prebiopsy MRI of the prostate. CONCLUSIONS: Non-Hispanic Black patients with prostate cancer and those in less urban areas were less likely to have prebiopsy MRI of the prostate during its initial adoption as a tool for improving prostate cancer detection.

Confirmed Hypoglycemia Without Whipple Triad: A Rare Case of Hyper-Warburgism.

Spontaneous hypoglycemia in nondiabetic patients poses a diagnostic challenge. Hypoglycemia in malignancy has several etiologies; an extremely rare mechanism is the Warburg effect causing excess lactate production and avid glucose consumption. We describe the clinical course of a 52-year-old man admitted for chest wall mass and severe but asymptomatic hypoglycemia. Laboratory workup was obtained for insulin vs noninsulin-mediated hypoglycemia, and biopsy of the chest wall mass and 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG-PET/CT) scan were performed. D10 infusion and intravenous/oral steroids started for severe hypoglycemia. Chemotherapy was initiated after biopsy, and blood glucose (BG) and lactate levels followed with clinical response in tumor size and changes in PET/CT. Investigations were significant for venous BG in the 40s (Ademolus Classification of Hypoglycemia grade 2 hypoglycemia), plasma insulin of less than 2 µU/mL (2-20 µU/mL), C-peptide of 0.2 ng/mL (0.8-6.0 ng/mL), insulin-like growth factor 2 (IGF-2) of 113 ng/mL (333-967 ng/mL), serum lactate of 16 mmol/L (0.5-2 mmol/L), and albumin of 2.3 g/dL (3.4-5.4 g/dL). Biopsy showed diffuse large B-cell lymphoma, and PET revealed highly FDG-avid disease in the chest, abdomen, and pelvis, but no FDG uptake was seen in the brain. Hypoglycemia and lactic acidosis improved remarkably after chemotherapy. PET/CT at 4 weeks showed complete metabolic response with reappearance of physiological FDG uptake in the brain. Noninsulin-mediated hypoglycemia was likely due to the combination of profound malnutrition and rapid glucose use by cancer cells. The patient presented with exaggerated Warburg effect (hyper-Warburgism), evident by extreme glucose consumption, severe lactic acidosis, and large tumor burden on PET/CT. Absence of cognitive symptoms was probably due to use of lactate by the brain. Chemotherapy corrected these abnormalities rapidly, and must be instituted in a timely manner.

Influence of excess weight on lower-extremity vertical stiffness and metabolic cost of walking.

The purpose was to test whether lower-extremity vertical stiffness and gait mechanics explain differences in energy cost of walking (Cw) between individuals with normal weight (NW) and obesity (OB). Ten OB (33.1 ± 2.0 kg m-2) and 10 NW (24.2 ± 1.3 kg m-2) walked for six minutes on an instrumented treadmill at 1.25 m s-1 while Cw, lower-extremity kinematics, and vertical stiffness (K vert) were measured. NW completed another trial with a loaded vest (NWL) to simulate the BMI of the obese group. Cw was 24% greater in OB (277.5 ± 45.3 J m-1) and 23% greater in NWL (272.7 ± 35.7 J m-1) than NW (211.0 ± 27.0 J m-1, P < 0.005). Mass-specific Cw (Cwkg) wasn't different between conditions (P = 0.085). Lower-extremity K vert was 40% higher in OB (32.7 ± 5.2 kN m-1) than NW (23.3 ± 4.7 kN m-1, P < 0.001), but neither was different from NWL (27.5 ± 3.4 kN m-1, P > 0.05). Mass-specific K vert (P = 0.081) was similar across conditions. K vert was related to Cw (r = 0.55, P = 0.001). Cwkg wasn't different between NW or OB, but there was a negative correlation between BMI and Cwkg driven by lower Cwkg in NWL. Cw and K vert covaried in proportion to body mass, but mass-specific K vert was unrelated to Cwkg. Mass-specific K vert was lower in NWL than OB due to NWL's greater angle of attack, center of mass displacement, and joint range of motion.

Identifying Patient Characteristics Associated With Deficits in Surgical Decision Making.

BACKGROUND: Patient involvement in surgical decisions is formalized in the informed consent process, which should reflect that the patient understands their diagnosis, planned procedure, and the associated risks and benefits before consenting to treatment. If high-quality shared decision making has occurred, the treatment chosen should best match the goals and preferences of the patient. Little information currently exists that analyzes factors associated with decisional quality in surgery. Identifying patient factors correlated with specific deficits in preoperative decision making is essential for improvement of the shared decision-making process. This study aims to identify patient characteristics and coping strategies associated with the presence of knowledge deficits regarding their diagnosis and procedure so that interventions can be targeted to these vulnerable groups. METHODS: Approximately 882 preoperative patients were assessed regarding understanding of their diagnosis and procedure. Sociodemographic and decision-making variables were evaluated using validated measures. Univariate analysis and logistic regression models assessed factors associated with lower decisional quality. RESULTS: Approximately 136 (15%) of 882 patients had deficits in knowledge of diagnosis and/or procedure. Older patients were more likely to demonstrate these deficits (P = 0.0002). Using multivariate analysis, independent predictors of knowledge deficits included patients who identified themselves as Black, Asian, or other race (odds ratio [OR], 2.63; 95% confidence interval [CI], 1.19-5.85; and OR, 1.88; 95% CI, 1.00-3.55, respectively); were older (OR, 1.02; 95% CI, 1.01-1.04); and used denial as a coping strategy (OR, 2.61; 95% CI, 1.29-5.28). The use of acceptance as a coping strategy negatively predicted knowledge deficits (OR, 0.55; 95% CI, 0.36-0.84). CONCLUSIONS: Specific patient factors and coping strategies are associated with deficiencies in decisional quality. Identifying vulnerable groups at risk for these issues can help target methodologies and resources to ensure high-quality surgical decision making.

Hot isostatic pressing (HIP) to achieve isotropic microstructure and retain as-built strength in an additive manufacturing titanium alloy (Ti-6Al-4V).

Hot isostatic pressing (HIP) treatments are traditionally used to seal internal porosity, because defects exist in as-built Ti-6Al-4V parts produced by electron-beam melting powder-bed fusion. Standard HIP treatment of Ti-6Al-4V parts results in decreased strength due to coarsening of the microstructure. We present a new HIP strategy with the following steps: hold above the ß-transus, rapid quenching, and tempering. This new HIP treatment seals internal porosity, causes a columnar-to-equiaxed transition in morphology of prior-ß grains, changes the α lath aspect ratio, removes microstructural heterogeneities and matches the yield and ultimate tensile strength of the as-built condition.

A novel anesthesiologist-led multidisciplinary model for evaluating high-risk surgical patients at a comprehensive cancer center.

The objective of this retrospective analysis was to describe the development and implementation of an anesthesiologist-led multidisciplinary committee to evaluate high-risk surgical patients in order to improve surgical appropriateness. The study was conducted in an anesthesia preoperative evaluation clinic at an academic comprehensive cancer center. One hundred sixty-seven high-risk surgical patients with cancer-related diagnoses were evaluated and discussed at a High-Risk Committee (HRC) meeting to determine surgical appropriateness and optimize perioperative care. The HRC is an anesthesiologist-led model for multidisciplinary review of high-risk patients developed at Roswell Park Comprehensive Cancer Center. The group of high-risk patients in which surgery was not performed had, on average, a greater percentage of hypertension, smoking history, dyspnea, heart failure, chronic obstructive pulmonary disease, diabetes, renal failure, and sleep apnea than the group in whom surgery was performed. Only one of 107 high-risk patients who had surgery died within the first 30 days after surgery. A smaller percentage of patients died in the group that had surgery versus the group in which surgery was canceled. For all patients discussed by the HRC, the mortality was less than 2% within the first 30 days after the HRC.

Creating a Pathway for Multidisciplinary Shared Decision-Making to Improve Communication During Preoperative Assessment.

Shared decision-making (SDM) is essential for high-quality surgical care. Barriers to SDM exist in clinical practice but there is evidence these obstacles can be overcome. SDM requires clinician and patient engagement. Though patients may indicate understanding, deficits in decision making may persist based on language, age, or educational barriers. Multidisciplinary decision-making before surgery is an opportunity for anesthesiologists and other perioperative professionals to improve surgical care. The authors present an example of a successfully implemented pathway for high-risk surgical patients at a tertiary care center, leveraging the preoperative anesthesia evaluation.

Factors associated with an increased risk of perioperative cardiac arrest in emergent and elective craniotomy and spine surgery.

OBJECTIVE: Cardiac arrest following neurosurgery is a devastating complication associated with significant postoperative morbidity and mortality. There are no published studies that have used a large and robust multicenter database to specifically examine demographic and surgical risk factors associated with cardiac arrests following craniotomy and spine surgeries, respectively. PATIENTS AND METHODS: We retrospectively analyzed data from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database for the period between January 1, 2007 and December 31, 2013, focusing on cardiac arrest associated with craniotomy and spine surgery from the intraoperative period to 30days after surgery. A total of 73,584 neurosurgical patients were analyzed (59,609 spine surgeries and 13,975 craniotomies). RESULTS: There was an increased risk of cardiac arrest for both craniotomy and spine surgeries in patients with American Society of Anesthesiologists (ASA) Physical Status class 4 or 5, Black and Asian patients compared to White patients and patients totally dependent versus independent based on the ACS-NSQIP risk calculator. The risk of cardiac arrest for craniotomy was 66.5 per 10,000 anesthetics and for spine surgery was 21.3 per 10,000 anesthetics. Cardiac arrest associated with emergent non-traumatic craniotomy was 36.5% and with emergent non-traumatic spine surgery was only 17.3%. We found that 18% of cardiac arrests for craniotomy and 25% of cardiac arrests for spine surgery occurred from the intraoperative period through postoperative day (POD) 0. Both craniotomy and spine surgery patients who had a cardiac arrest were more likely to have acute kidney injury (AKI), failure to wean from the ventilator, postoperative dialysis, myocardial infarction (MI), venous thromboembolism (VTE) and sepsis in the postoperative period. The overall mortality rate for both craniotomy and spine surgeries who had a cardiac arrest from the intraoperative period to 30days postoperative was 61.8% versus 1.2% in the no cardiac arrest control group. CONCLUSIONS: Identification of patient and surgery specific characteristics from ACS-NSQIP data associated with cardiac arrest following craniotomy and spine surgery may lead to initiatives to reduce morbidity and mortality in the neurosurgical patient population.